Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
Nusinersen recently became available as the first treatment for Spinal Muscular Atrophy (SMA) and data on its effectiveness and safety in adult SMA patients are still scarce. We evaluated the effectiveness and safety of nusinersen treatment during 14 months in 16 adult patients with SMA types 3 and 4 in a prospective study, and retrospectively detailed the natural history of 48 adult SMA patients types 2, 3 and 4. Hand grip strength (p = 0.03), hand motor function (p = 0.04) as assessed by a sub-score of the Revised Upper Limb Module (RULM) and the Medical Research Council (MRC) sum score (p = 0.04) improved significantly at month 14. Importantly, the MRC sum score had declined significantly (p < 0.01) prior to start of treatment in these patients. A minimal clinically important difference (MCID) in the Hammersmith Functional Motor Scale Expanded (HFMSE) and RULM scores was achieved in 31% and 50% of the patients, respectively, but the mean changes from baseline failed to reach significance. Forced Vital Capacity (FVC) transiently increased at month 6 (p = 0.01), whereas the Peak Expiratory Flow (PEF) did not. The Activity Limitations scale declined significantly prior to start of treatment (p < 0.01) and showed an improvement with nusinersen which was not significant. The safety evaluation did not reveal serious adverse events and no signs of nephrotoxicity or antisense oligonucleotide (ASO)-mediated inflammation. We conclude that hand grip strength and hand motor function, as well as MRC sum scores improved significantly in nusinersen-treated adult patients with SMA types 3 and 4.


A New Magnetic Topological Quantum Material Candidate by Design.
Magnetism, when combined with an unconventional electronic band structure, can give rise to forefront electronic properties such as the quantum anomalous Hall effect, axion electrodynamics, and Majorana fermions. Here we report the characterization of high-quality crystals of EuSn2P2, a new quantum material specifically designed to engender unconventional electronic states plus magnetism. EuSn2P2 has a layered, Bi2Te3-type structure. Ferromagnetic interactions dominate the Curie-Weiss susceptibility, but a transition to antiferromagnetic ordering occurs near 30 K. Neutron diffraction reveals that this is due to two-dimensional ferromagnetic spin alignment within individual Eu layers and antiferromagnetic alignment between layers-this magnetic state surrounds the Sn-P layers at low temperatures. The bulk electrical resistivity is sensitive to the magnetism. Electronic structure calculations reveal that EuSn2P2 might be a strong topological insulator, which can be a new magnetic topological quantum material (MTQM) candidate. The calculations show that surface states should be present, and they are indeed observed by angle-resolved photoelectron spectroscopy (ARPES) measurements.


Mobile phone use and risk for intracranial tumors and salivary gland tumors - A meta-analysis.
Results of epidemiological studies on the association between use of mobile phone and brain cancer are ambiguous, as well as the results of 5 meta-analysis studies published to date. Since the last meta-analysis (2009), new case-control studies have been published, which theoretically could affect the conclusions on this relationship. Therefore, we decided to perform a new meta-analysis. We conducted a systematic review of multiple electronic data bases for relevant publications. The inclusion criteria were: original papers, case-control studies, published till the end of March 2014, measures of association (point estimates as odds ratio and confidence interval of the effect measured), data on individual exposure. Twenty four studies (26 846 cases, 50 013 controls) were included into the meta-analysis. A significantly higher risk of an intracranial tumor (all types) was noted for the period of mobile phone use over 10 years (odds ratio (OR) = 1.324, 95% confidence interval (CI): 1.028-1.704), and for the ipsilateral location (OR = 1.249, 95% CI: 1.022-1.526). The results support the hypothesis that long-term use of mobile phone increases risk of intracranial tumors, especially in the case of ipsilateral exposure. Further studies are needed to confirm this relationship. Int J Occup Med Environ Health 2017;30(1)27-43.


Concealed lung anatomy in Botticelli's masterpieces the primavera and the birth of venus.
Sandro Botticelli was one of the most esteemed painters and draughtsmen among Renaissance artists. Under the patronage of the De' Medici family, he was active in Florence during the flourishing of the Renaissance trend towards the reclamation of lost medical and anatomical knowledge of ancient times through the dissection of corpses. Combining the typical attributes of the elegant courtly style with hallmarks derived from the investigation and analysis of classical templates, he left us immortal masterpieces, the excellence of which incomprehensibly waned and was rediscovered only in the 1890s. Few know that it has already been reported that Botticelli concealed the image of a pair of lungs in his masterpiece, The Primavera. The present investigation provides evidence that Botticelli embedded anatomic imagery of the lung in another of his major paintings, namely, The Birth of Venus. Both canvases were most probably influenced and enlightened by the neoplatonic philosophy of the humanist teachings in the De' Medici's circle, and they represent an allegorical celebration of the cycle of life originally generated by the Divine Wind or Breath. This paper supports the theory that because of the anatomical knowledge to which he was exposed, Botticelli aimed to enhance the iconographical meaning of both the masterpieces by concealing images of the lung anatomy within them.


Gene expression profiling and prediction of clinical outcome in ovarian cancer.
Epithelial ovarian cancer is the most lethal gynaecological cancer. Despite debulking surgery and platinum/taxane-based chemotherapy, the prognosis remains poor with approximately 25% 5-year survival. Current histo-clinical prognostic factors are insufficient to capture the complex cascade of events that drive the heterogeneous clinical behaviour of the disease. There is a crucial need to identify new prognostic subclasses of disease as well as new therapeutic targets. Today, DNA microarrays allow the simultaneous and quantitative analysis of the mRNA expression levels of thousands of genes in a tumour sample. They have been applied to ovarian cancer research for predicting initial surgical resectability, survival and response to first-line chemotherapy. The first results are promising. In this review, we describe recent applications of DNA microarrays in ovarian cancer research and discuss some issues to address in the near future to allow the technology to reach its full potential in clinical practice.


Ten-year trends in antibiotic usage at a tertiary care hospital in Korea, 2004 to 2013.
This study was performed to evaluate trends in antibiotic usage at a tertiary care hospital in Korea. This study collated antibiotic prescription data and total patient days for inpatients at a tertiary care hospital in Korea between 2004 and 2013. The consumption of each class of antibiotic was converted to defined daily dose (DDD)/1,000 patient-days. We defined 3rd generation cephalosporins, 4th generation cephalosporins, β-lactam/β-lactamase inhibitors, and fluoroquinolones as broad-spectrum antibiotics; carbapenems, tigecycline, glycopeptides, oxazolidinone, and polymyxin were defined as antibiotics against multidrug-resistant (MDR) pathogens. Other antibiotic classes were defined as nonbroad-spectrum antibiotics. Mean antibiotic consumption was 920.69 DDD/1,000 patient-days. The proportions of broad-spectrum antibiotics, antibiotics against MDR pathogens, and nonbroad-spectrum antibiotics were 41.8% (384.48/920.69), 3.5% (32.24/920.69), and 54.7% (503.97/920.69), respectively. Consumption of broad-spectrum antibiotics (coefficient for time 0.141; p = 0.049) and antibiotics against MDR pathogens (coefficient for time 0.185; p < 0.001) showed a significant increasing trend over the study period. Nonbroad-spectrum antibiotic consumption showed a significant decreasing trend over the study period (coefficient for time -2.601; p < 0.001). Over the 10-year period, a stepwise increase in the consumption of broad-spectrum antibiotics and antibiotics against MDR pathogens was observed at a tertiary care hospital in Korea. Conversely, during the same period, nonbroad-spectrum antibiotic consumption showed a significant decreasing trend.


Similarity of visual selectivity among clonally related neurons in visual cortex.
Neurons in rodent visual cortex are organized in a salt-and-pepper fashion for orientation selectivity, but it is still unknown how this functional architecture develops. A recent study reported that the progeny of single cortical progenitor cells are preferentially connected in the postnatal cortex. If these neurons acquire similar selectivity through their connections, a salt-and-pepper organization may be generated, because neurons derived from different progenitors are intermingled in rodents. Here we investigated whether clonally related cells have similar preferred orientation by using a transgenic mouse, which labels all the progeny of single cortical progenitor cells. We found that preferred orientations of clonally related cells are similar to each other, suggesting that cell lineage is involved in the development of response selectivity of neurons in the cortex. However, not all clonally related cells share response selectivity, suggesting that cell lineage is not the only determinant of response selectivity.


Effect of age and sex on efficacy and tolerability of β blockers in patients with heart failure with reduced ejection fraction: individual patient data meta-analysis.
To determine the efficacy and tolerability of β blockers in a broad age range of women and men with heart failure with reduced ejection fraction (HFrEF) by pooling individual patient data from placebo controlled randomised trials. Prospectively designed meta-analysis of individual patient data from patients aged 40-85 in sinus rhythm at baseline, with left ventricular ejection fraction <0.45. 13,833 patients from 11 trials; median age 64; 24% women. The primary outcome was all cause mortality; the major secondary outcome was admission to hospital for heart failure. Analysis was by intention to treat with an adjusted one stage Cox proportional hazards model. Compared with placebo, β blockers were effective in reducing mortality across all ages: hazard ratios were 0.66 (95% confidence interval 0.53 to 0.83) for the first quarter of age distribution (median age 50); 0.71 (0.58 to 0.87) for the second quarter (median age 60); 0.65 (0.53 to 0.78) for the third quarter (median age 68); and 0.77 (0.64 to 0.92) for the fourth quarter (median age 75). There was no significant interaction when age was modelled continuously (P=0.1), and the absolute reduction in mortality was 4.3% over a median follow-up of 1.3 years (number needed to treat 23). Admission to hospital for heart failure was significantly reduced by β blockers, although this effect was attenuated at older ages (interaction P=0.05). There was no evidence of an interaction between treatment effect and sex in any age group. Drug discontinuation was similar regardless of treatment allocation, age, or sex (14.4% in those give β blockers, 15.6% in those receiving placebo). Irrespective of age or sex, patients with HFrEF in sinus rhythm should receive β blockers to reduce the risk of death and admission to hospital.Registration PROSPERO CRD42014010012; Clinicaltrials.gov NCT00832442.


Low-frequency cortical oscillations are modulated by temporal prediction and temporal error coding.
Monitoring and updating temporal predictions are critical abilities for adaptive behavior. Here, we investigated whether neural oscillations are related to violation and updating of temporal predictions. Human participants performed an experiment in which they had to generate a target at an expected time point, by pressing a button while taking into account a variable delay between the act and the stimulus occurrence. Our behavioral results showed that participants quickly adapted their temporal predictions in face of an error. Concurrent electrophysiological (EEG) data showed that temporal errors elicited markers that are classically related to error coding. Furthermore, intertrial phase coherence of frontal theta oscillations was modulated by error magnitude, possibly indexing the degree of surprise. Finally, we found that delta phase at stimulus onset was correlated with future behavioral adjustments. Together, our findings suggest that low frequency oscillations play a key role in monitoring and in updating temporal predictions.


Scaffolding young Australian women's journey to motherhood: a narrative understanding.
Pregnant and young mothers' stories often go untold within community social and health service policy, planning and practice. Consequently, there is a significant gap between young women's experiences of motherhood and current service provision. This study was undertaken in response to a paucity of observational and contextually rich research that explores young women's experiences of pregnancy and motherhood, including the role a community service played in scaffolding their motherhood journeys. Fundamental to this study's purpose was the premise that to improve planning and delivery of more appropriate services for this group, we need to listen, consult and consider what life is like for young mothers. The purpose of this paper is to describe the role a community service played in scaffolding young women's experiences as they transitioned to motherhood. Using a narrative approach, this study draws on data collected from contextual observations of 31 informants and 11 in-depth interviews over 7 months of fieldwork in 2010 at a community service in the Peel region of Western Australia. The integral role a community service played in the young women's transition to motherhood was analysed thematically and captured in three metaphorical themes, finding a circle of friends, weaving a tapestry and turning the page. The young women's storied experiences of motherhood present a strong argument for radical re-visioning of community and social health policy, practice and service delivery for young mothers. The findings revealed that judgement-free services that foster social and supportive relationships were integral in developing positive motherhood identities. The power of narrative and social learning when working with young mothers suggests that social models of health that foster a relational, narrative approach to practice are fundamental to young mothers finding their own voices and solutions and becoming active agents in re-authoring future narratives of hope, autonomy and agency.


The potential for self-seeding by the coral Pocillopora spp. in Moorea, French Polynesia.
Coral reefs in Moorea, French Polynesia, suffered catastrophic coral mortality through predation by Acanthaster planci from 2006 to 2010, and Cyclone Oli in 2010, yet by 2015 some coral populations were approaching pre-disturbance sizes. Using long-term study plots, we quantified population dynamics of spawning Pocillopora spp. along the north shore of Moorea between 2010 and 2014, and considered evidence that population recovery could be supported by self-seeding. Results scaled up from study plots and settlement tiles suggest that the number of Pocillopora spp. colonies on the outer reef increased 1,890-fold between 2010 and 2014/2015, and in the back reef, 8-fold between 2010 and 2014/2015. Assuming that spawning Pocillopora spp. in Moorea release similar numbers of eggs as con-generics in Hawaii, and fertilization success is similar to other spawning corals, the capacity of Pocillopora spp. to produce larvae was estimated. These estimates suggest that Pocillopora spp. in Moorea produced a large excess of larvae in 2010 and 2014 relative to the number required to produce the recruits found in the back reef and outer reef in 2010 and 2014, even assuming that ∼99.9% of the larvae do not recruit in Moorea. Less than a third of the recruits in one year would have to survive to produce the juvenile Pocillopora spp. found in the back and outer reefs in 2010 and 2014/2015. Our first order approximations reveal the potential for Pocillopora spp. on the north shore of Moorea to produce enough larvae to support local recruitment and population recovery following a catastrophic disturbance.


Prostaglandin E2 enhances and gamma interferon inhibits germ tube formation in Candida albicans.
Prostaglandin E2 (PGE2), an immunosuppressive monokine that increases intracellular cyclic AMP (cAMP) levels, stimulated Candida albicans germ tube formation. Dibutyryl cAMP (dB-cAMP) and isoproterenol, other compounds that increase cAMP levels, also stimulated germination. Gamma interferon (IFN-gamma), a product of cellular immune system activation, inhibited Candida germ tube formation, even in the presence of PGE2, dB-cAMP, and isoproterenol. Thus, PGE2 and IFN-gamma as well as having opposing roles in the suppression or activation of cell-mediated immunity, are also antagonists for the yeast-to-hyphal transition of C. albicans.


Regional distribution of astrocytes with intense immunoreactivity for glutamate dehydrogenase in rat brain: implications for neuron-glia interactions in glutamate transmission.
The principally mitochondrial enzyme glutamate dehydrogenase (GDH) exhibited low-intensity, uniform immunoreactivity in neurons and intense heterogeneous labeling of glial cells of rat brain. Simultaneous peroxidase labeling for GDH and immunoautoradiography for glial fibrillary acidic protein (GFAP) confirmed the astrocytic localization of the enzyme. Immunoreactivity in astrocytes, but not in neurons, required the presence of Triton X-100 as a solubilizing agent. Most of the intensely labeled glial processes were localized to regions previously reported as containing moderate to high densities of binding sites for the excitatory amino acids, L-glutamate or L-aspartate, and glutamatergic fibers. These included several forebrain regions, such as the superficial layers of the rostral neocortex, dorsal neostriatum, nucleus accumbens, septohippocampal nucleus, intralaminar thalamic nuclei, and external capsules. However, the central gray of the midbrain, the nuclei of the reticular formation, brain stem regions projecting to the cerebellum, and cranial nuclei of the trigeminal and vagal nerves also exhibited intense glial labeling for GDH, even though some of these regions are known to receive only weak glutamatergic projections. A second factor determining the distribution of GDH appeared to be neuronal activity, as assessed by correspondence with reported high densities of cytochrome oxidase. We conclude that GDH enriched in glial populations exists in a subcellular compartment distinct from that of neurons and may serve as one of the enzymes involved in glutamatergic transmission. Deficiencies of glial GDH and the consequent cytotoxic effects of high levels of excitatory amino acids may contribute to a number of neurodegenerative disorders.


Simultaneous detection of single nucleotide polymorphisms and copy number variations in the CYP2D6 gene by multiplex polymerase chain reaction combined with capillary electrophoresis.
CYP2D6 (cytochrome P450 2D6) is one of the most important enzymes involved in drug metabolism, and CYP2D6 gene variants may cause toxic effects of therapeutic drugs or treatment failure. In this research, a rapid and simple method for genotyping the most common mutant alleles in the Asian population (CYP2D6*1/*1, CYP2D6*1/*10, CYP2D6*10/*10, CYP2D6*1/*5, CYP2D6*5/*10, and CYP2D6*5/*5) was developed by allele-specific polymerase chain reaction (AS-PCR) combined with capillary electrophoresis (CE). We designed a second mismatch nucleotide next to the single nucleotide polymorphism (SNP) site in allele-specific primers to increase the difference in PCR amplification. Besides, we established simulation equations to predict the CYP2D6 genotypes by analyzing the DNA patterns in the CE chromatograms. The multiplex PCR combined with CE method was applied to test 50 patients, and all of the test results were compared with the DNA sequencing method, long-PCR method and real-time PCR method. The correlation of the analytical results between the proposed method and other methods were higher than 90%, and the proposed method is superior to other methods for being able to simultaneous detection of SNPs and copy number variations (CNV). Furthermore, we compared the plasma concentration of aripiprazole (a CYP2D6 substrate) and its major metabolites with the genotype of 25 patients. The results demonstrate the proposed genotyping method is effective for estimating the activity of the CYP2D6 enzyme and shows potential for application in personalized medicine. Similar approach can be applied to simultaneous detection of SNPs and CNVs of other genes.


Identification of putative MAPK kinases in Oryza minuta and O. sativa responsive to biotic stresses.
The mitogen-activated protein kinase (MAPK) signaling cascade is critical for regulating plant defense systems against various kinds of pathogen and environmental stresses. One component of this cascade, the MAP kinase kinases (MAPKK), has not yet been shown to be induced in plants following biotic attacks, such as those by insects and fungi. We describe here a gene coding for a blast (Magnaporthe grisea)- and insect (Nilaparvata lugens)-responsive putative MAPK kinase, OmMKK1 (Oryza minuta MAPKK 1), which was identified in a library of O. minuta expressed sequence tags (ESTs). Two copies of OmMKK1 are present in the O. minuta genome. They encode a predicted protein with molecular mass 39 kDa and pI of 6.2. Transcript patterns following imbibition of plant hormones such as methyl jasmonic acid (MeJA), ethephone, salicylic acid (SA) and abscisic acid (ABA), as well as exposure to methyl viologen (MV), revealed that the expression of OmMKK1 is related to defense response signaling pathways. A comparative analysis of OmMKK1 and its O. sativa ortholog OsMKK1 showed that both were induced by stress-related hormones and biotic stresses, but that the kinetics of their responses differed despite their high amino acid sequence identity (96%).


Visfatin induces sickness responses in the brain.
Visfatin, also known as nicotiamide phosphoribosyltransferase or pre-B cell colony enhancing factor, is a pro-inflammatory cytokine whose serum level is increased in sepsis and cancer as well as in obesity. Here we report a pro-inflammatory role of visfatin in the brain, to mediate sickness responses including anorexia, hyperthermia and hypoactivity. Rats were intracerebroventricularly (ICV) injected with visfatin, and changes in food intake, body weight, body temperature and locomotor activity were monitored. Real-time PCR was applied to determine the expressions of pro-inflammatory cytokines, proopiomelanocortin (POMC) and prostaglandin-synthesizing enzymes in their brain. To determine the roles of cyclooxygenase (COX) and melanocortin in the visfatin action, rats were ICV-injected with visfatin with or without SHU9119, a melanocortin receptor antagonist, or indomethacin, a COX inhibitor, and their sickness behaviors were evaluated. Administration of visfatin decreased food intake, body weight and locomotor activity and increased body temperature. Visfatin evoked significant increases in the levels of pro-inflammatory cytokines, prostaglandin-synthesizing enzymes and POMC, an anorexigenic neuropeptide. Indomethacin attenuated the effects of visfatin on hyperthermia and hypoactivity, but not anorexia. Further, SHU9119 blocked visfatin-induced anorexia but did not affect hyperthermia or hypoactivity. Visfatin induced sickness responses via regulation of COX and the melanocortin pathway in the brain.


Global/local processing of hierarchical visual stimuli in a conflict-choice task by capuchin monkeys (Sapajus spp.).
In the last two decades, comparative research has addressed the issue of how the global and local levels of structure of visual stimuli are processed by different species, using Navon-type hierarchical figures, i.e. smaller local elements that form larger global configurations. Determining whether or not the variety of procedures adopted to test different species with hierarchical figures are equivalent is of crucial importance to ensure comparability of results. Among non-human species, global/local processing has been extensively studied in tufted capuchin monkeys using matching-to-sample tasks with hierarchical patterns. Local dominance has emerged consistently in these New World primates. In the present study, we assessed capuchins' processing of hierarchical stimuli with a method frequently adopted in studies of global/local processing in non-primate species: the conflict-choice task. Different from the matching-to-sample procedure, this task involved processing local and global information retained in long-term memory. Capuchins were trained to discriminate between consistent hierarchical stimuli (similar global and local shape) and then tested with inconsistent hierarchical stimuli (different global and local shapes). We found that capuchins preferred the hierarchical stimuli featuring the correct local elements rather than those with the correct global configuration. This finding confirms that capuchins' local dominance, typically observed using matching-to-sample procedures, is also expressed as a local preference in the conflict-choice task. Our study adds to the growing body of comparative studies on visual grouping functions by demonstrating that the methods most frequently used in the literature on global/local processing produce analogous results irrespective of extent of the involvement of memory processes.


Vection during conflicting multisensory information about the axis, magnitude, and direction of self-motion.
We examined the vection induced by consistent and conflicting multisensory information about self-motion. Observers viewed displays simulating constant-velocity self-motion in depth while physically oscillating their heads left-right or back-forth in time with a metronome. Their tracked head movements were either ignored or incorporated directly into the self-motion display (as an added simulated self-acceleration). When this head oscillation was updated into displays, sensory conflict was generated by simulating oscillation along: (i) an orthogonal axis to the head movement; or (ii) the same axis, but in a non-ecological direction. Simulated head oscillation always produced stronger vection than 'no display oscillation'--even when the axis/direction of this display motion was inconsistent with the physical head motion. When head-and-display oscillation occurred along the same axis: (i) consistent (in-phase) horizontal display oscillation produced stronger vection than conflicting (out-of-phase) horizontal display oscillation; however, (ii) consistent and conflicting depth oscillation conditions did not induce significantly different vection. Overall, orthogonal-axis oscillation was found to produce very similar vection to same-axis oscillation. Thus, we conclude that while vection appears to be very robust to sensory conflict, there are situations where sensory consistency improves vection.


Impact of Weekend Presentation on Short-Term Outcomes and Choice of Clipping vs Coiling in Subarachnoid Hemorrhage.
Presentation on a weekend is commonly associated with higher mortality and a decreased likelihood of receiving invasive procedures. To determine whether weekend presentation influences mortality, discharge destination, or type of treatment received (clip vs coil) in subarachnoid hemorrhage (SAH). We performed a serial cross-sectional retrospective study using the Nationwide Inpatient Sample. All adult discharges with a primary diagnosis of SAH (ICD-9-CM 435) from 2005 to 2010 were included, and records with trauma or arteriovenous malformation were excluded. Unadjusted and adjusted associations between weekend presentation and 3 outcomes (in-hospital mortality, discharge destination, and treatment with clip vs coil) were estimated using chi-square tests and multilevel logistic regression. A total of 46 093 admissions for nontraumatic SAH were included in the sample; 24.6% presented on a weekend, 68.9% on a weekday, and 6.5% had unknown day of presentation. Weekend admission was not a significant predictor of inpatient mortality (25.4% weekend vs 24.9% weekday; P = .44), or a combined poor outcome measure of mortality or discharge to long-term acute care or hospice (30.3% weekend vs 29.4% weekday; P = .23). Among those treated for aneurysm obliteration, the proportion of clipped vs coiled did not change with weekend vs weekday presentation (21.5% clipped with weekend presentation vs 21.6% weekday, P = .95; 21.5% coiled with weekend presentation vs 22.4% weekday, P = .19). Presentation with nontraumatic SAH on a weekend did not influence mortality, discharge destination, or type of treatment received (clip vs coil) compared with weekday presentation.


Collective behavior of antagonistically acting kinesin-1 motors.
In many subcellular force-generating systems, groups of motor proteins act antagonistically. Here, we present an experimental study of the tug of war between superprocessive kinesin-1 motors acting on antiparallel microtubule doublets in vitro. We found distinct modes of slow and fast movements, as well as sharp transitions between these modes and regions of coexistence. We compare our experimental results to a quantitative theory based on the physical properties of individual motors. Our results show that mechanical interactions between motors can collectively generate coexisting transport regimes with distinct velocities.


Identification and characterization of 2 testicular germ cell markers, Glut3 and CyclinA2.
Testicular germ cell tumors (TGCT) are the most common type of testicular tumor and encompass different histologic types that greatly influence treatment and prognosis. Immunohistochemical studies may be required for accurate classification, particularly when these tumors present at extragonadal sites, and to aid in distinguishing histologic types. Traditional markers for identifying and distinguishing TGCT include PLAP, CD117, AFP, and CD30. More recently, the addition of OCT3/4 and SALL4 has increased sensitivity for immunohistochemical detection of germ cell tumors. We examined gene expression data from a previously published microarray study that compared normal testis mRNA expression to various TGCT. We also performed a search of the literature to identify less well-characterized markers. Glut3 and cyclinA2 showed promise as TGCT markers. Therefore, we evaluated expression of glut3 and cyclinA2 by immunohistochemistry using tissue microarrays (TMAs). Of 66 seminomas included in the TMA, 64 (97%) showed positive nuclear staining for cyclinA2 and 58 (88%) were strongly positive. Strong positive staining for cyclinA2 was also seen in the spermatocytic seminoma. All 20 of the embryonal carcinomas stained positively with cyclinA2, and 19 (95%) displayed strong nuclear staining for cyclinA2. Twenty of the 20 embryonal carcinomas stained for glut3 in a strong membranous pattern. Of 8 yolk sac tumors, 100% stained with glut3. We also evaluated glut3 and cyclinA2 staining on a general TMA containing 486 samples representing 156 different tumors. CyclinA2 stained a number of other tumor types, but the majority of these were weak or focal staining. Glut3 was rarely positive in other tumors; interestingly, most of these were of ovarian origin. We conclude that glut3 is a sensitive (96%) and specific (92%) marker for embryonal carcinomas and yolk sac tumors. Although cyclinA2 is a sensitive marker of seminomas and embryonal carcinomas (98%), its specificity is lower if focal and weak staining of nongerm cell tumors is considered positive. The sensitivity and specificity of glut3 are comparable with that seen for SALL4.


Rubisco catalytic properties of wild and domesticated relatives provide scope for improving wheat photosynthesis.
Rubisco is a major target for improving crop photosynthesis and yield, yet natural diversity in catalytic properties of this enzyme is poorly understood. Rubisco from 25 genotypes of the Triticeae tribe, including wild relatives of bread wheat (Triticum aestivum), were surveyed to identify superior enzymes for improving photosynthesis in this crop. In vitro Rubisco carboxylation velocity (V c), Michaelis-Menten constants for CO2 (K c) and O2 (K o) and specificity factor (S c/o) were measured at 25 and 35 °C. V c and K c correlated positively, while V c and S c/o were inversely related. Rubisco large subunit genes (rbcL) were sequenced, and predicted corresponding amino acid differences analysed in relation to the corresponding catalytic properties. The effect of replacing native wheat Rubisco with counterparts from closely related species was analysed by modelling the response of photosynthesis to varying CO2 concentrations. The model predicted that two Rubisco enzymes would increase photosynthetic performance at 25 °C while only one of these also increased photosynthesis at 35 °C. Thus, under otherwise identical conditions, catalytic variation in the Rubiscos analysed is predicted to improve photosynthetic rates at physiological CO2 concentrations. Naturally occurring Rubiscos with superior properties amongst the Triticeae tribe can be exploited to improve wheat photosynthesis and crop productivity.


Orientation tuning properties of simple cells in area V1 derived from an approximate analysis of nonlinear neural field models.
We present a general approximation method for the mathematical analysis of spatially localized steady-state solutions in nonlinear neural field models. These models comprise several layers of excitatory and inhibitory cells. Coupling kernels between and inside layers are assumed to be gaussian shaped. In response to spatially localized (i.e., tuned) inputs, such networks typically reveal stationary localized activity profiles in the different layers. Qualitative properties of these solutions, like response amplitudes and tuning widths, are approximated for a whole class of nonlinear rate functions that obey a power law above some threshold and that are zero below. A special case of these functions is the semilinear function, which is commonly used in neural field models. The method is then applied to models for orientation tuning in cortical simple cells: first, to the one-layer model with "difference of gaussians" connectivity kernel developed by Carandini and Ringach (1997) as an abstraction of the biologically detailed simulations of Somers, Nelson, and Sur (1995); second, to a two-field model comprising excitatory and inhibitory cells in two separate layers. Under certain conditions, both models have the same steady states. Comparing simulations of the field models and results derived from the approximation method, we find that the approximation well predicts the tuning behavior of the full model. Moreover, explicit formulas for approximate amplitudes and tuning widths in response to changing input strength are given and checked numerically. Comparing the network behavior for different nonlinearities, we find that the only rate function (from the class of functions under study) that leads to constant tuning widths and a linear increase of firing rates in response to increasing input is the semilinear function. For other nonlinearities, the qualitative network response depends on whether the model neurons operate in a convex (e.g., x(2)) or concave (e.g., sqrt(x)) regime of their rate function. In the first case, tuning gradually changes from input driven at low input strength (broad tuning strongly depending on the input and roughly linear amplitudes in response to input strength) to recurrently driven at moderate input strength (sharp tuning, supralinear increase of amplitudes in response to input strength). For concave rate functions, the network reveals stable hysteresis between a state at low firing rates and a tuned state at high rates. This means that the network can "memorize" tuning properties of a previously shown stimulus. Sigmoid rate functions can combine both effects. In contrast to the Carandini-Ringach model, the two-field model further reveals oscillations with typical frequencies in the beta and gamma range, when the excitatory and inhibitory connections are relatively strong. This suggests a rhythmic modulation of tuning properties during cortical oscillations.


Occupational inequality in health expectancy in Denmark.
Background: The pension age in Denmark is adjusted in line with projected increasing life expectancy without taking health differentials between occupational groups into account. The purpose was to study occupational disparities in partial life expectancy and health expectancy between the ages of 50 and 75. Methods: Register data on occupation and mortality were combined with data from the Danish part of Survey of Health, Ageing and Retirement in Europe in 2010-2014 (N=3179). Expected lifetime without and with activity limitations and without and with long-term illness was estimated by Sullivan's method and comparisons made between four occupational groups. Results: We found clear differences between occupational groups. Expected lifetime without activity limitations between the ages of 50 and 75 was about 4.5 years longer for men and women in high skilled white-collar occupations than for men and women in low skilled blue-collar occupations. Men in high skilled blue-collar and low skilled white-collar occupations could expect 2.3 and 3.8 years shorter lifetimes without activity limitations, respectively, than men in high skilled white-collar occupations. For women in low skilled white-collar occupations, lifetime without activity limitations was 2.6 years shorter than for women in high skilled white-collar occupations. Due to few observations, no results were obtained for women in the high skilled blue-collar group. The social gradient was also significant when health was measured by years without long-term illness. Conclusions: The results support implementation of a flexible pension scheme to take into account the health differentials between occupational groups.


Physical interventions to interrupt or reduce the spread of respiratory viruses.
Viral epidemics or pandemics of acute respiratory infections like influenza or severe acute respiratory syndrome pose a global threat. Antiviral drugs and vaccinations may be insufficient to prevent their spread. To review the effectiveness of physical interventions to interrupt or reduce the spread of respiratory viruses. We searched The Cochrane Library, the Cochrane Central Register of Controlled Trials (CENTRAL 2010, Issue 3), which includes the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to October 2010), OLDMEDLINE (1950 to 1965), EMBASE (1990 to October 2010), CINAHL (1982 to October 2010), LILACS (2008 to October 2010), Indian MEDLARS (2008 to October 2010) and IMSEAR (2008 to October 2010). In this update, two review authors independently applied the inclusion criteria to all identified and retrieved articles and extracted data. We scanned 3775 titles, excluded 3560 and retrieved full papers of 215 studies, to include 66 papers of 67 studies. We included physical interventions (screening at entry ports, isolation, quarantine, social distancing, barriers, personal protection, hand hygiene) to prevent respiratory virus transmission. We included randomised controlled trials (RCTs), cohorts, case-controls, before-after and time series studies. We used a standardised form to assess trial eligibility. We assessed RCTs by randomisation method, allocation generation, concealment, blinding and follow up. We assessed non-RCTs for potential confounders and classified them as low, medium and high risk of bias. We included 67 studies including randomised controlled trials and observational studies with a mixed risk of bias. A total number of participants is not included as the total would be made up of a heterogenous set of observations (participant people, observations on participants and countries (object of some studies)). The risk of bias for five RCTs and most cluster-RCTs was high. Observational studies were of mixed quality. Only case-control data were sufficiently homogeneous to allow meta-analysis. The highest quality cluster-RCTs suggest respiratory virus spread can be prevented by hygienic measures, such as handwashing, especially around younger children. Benefit from reduced transmission from children to household members is broadly supported also in other study designs where the potential for confounding is greater. Nine case-control studies suggested implementing transmission barriers, isolation and hygienic measures are effective at containing respiratory virus epidemics. Surgical masks or N95 respirators were the most consistent and comprehensive supportive measures. N95 respirators were non-inferior to simple surgical masks but more expensive, uncomfortable and irritating to skin. Adding virucidals or antiseptics to normal handwashing to decrease respiratory disease transmission remains uncertain. Global measures, such as screening at entry ports, led to a non-significant marginal delay in spread. There was limited evidence that social distancing was effective, especially if related to the risk of exposure. Simple and low-cost interventions would be useful for reducing transmission of epidemic respiratory viruses. Routine long-term implementation of some measures assessed might be difficult without the threat of an epidemic.


Light-triggered beta-hairpin folding and unfolding.
A light-switchable peptide is transformed with ultrashort pulses from a beta-hairpin to an unfolded hydrophobic cluster and vice versa. The structural changes are monitored by mid-IR probing. Instantaneous normal mode analysis with a Hamiltonian combining density functional theory with molecular mechanics is used to interpret the absorption transients. Illumination of the beta-hairpin state triggers an unfolding reaction that visits several intermediates and reaches the unfolded state within a few nanoseconds. In this unfolding reaction to the equilibrium hydrophobic cluster conformation, the system does not meet significant barriers on the free-energy surface. The reverse folding process takes much longer because it occurs on the time scale of 30 micros. The folded state has a defined structure, and its formation requires an extended search for the correct hydrogen-bond pattern of the beta-strand.


Spontaneous and specific binding of enterohemorrhagic Escherichia coli to overoxidized polypyrrole-coated microspheres.
Specific identification of enterohemorrhagic Escherichia coli was achieved using microspheres coated with overoxidized polypyrrole. The microspheres are well dispersed in aqueous media, and they specifically, spontaneously, and efficiently bind E. coli O157:H7 through surface area effects. In addition, we found that light-scattering by a single microsphere depended linearly on the number of bound cells.


Topical testosterone treatment for chronic allograft failure in liver transplant recipients with recurrent hepatitis C virus.
Liver transplant recipients with allograft failure due to recurrent hepatitis C virus (HCV) infection often develop marked muscle wasting and ascites prior to death and are denied repeat liver transplantation. We sought to determine whether topical testosterone therapy is associated with improved muscle mass and survival in patients with chronic allograft failure post-liver transplant. We performed a retrospective review of liver transplant recipients with chronic allograft failure. Group 1 patients were treated for >6 months with testosterone gel 1%; group 2 patients were untreated. Fourteen patients were identified with stage 3 or 4 fibrosis, muscle wasting, and allograft failure due to recurrent HCV. Group 1 (n=9) patients had statistically significant improvement in albumin, testosterone, muscle strength, well-being, and MELD/CTP scores, while there was no improvement seen for any of these parameters in group 2 (n=5). There were no deaths in group 1, while four of five patients in group 2 died on average 84 days posttransplant. Adverse effects of testosterone treatment included lower extremity edema (which resolved upon dose adjustment), hypertension, and pruritus. Topical testosterone gel appears to increase muscle strength, stimulate albumin synthesis, and improve survival in patients with allograft failure post-liver transplant.


Wingate Anaerobic Test Percentile Norms in Colombian Healthy Adults.
The Wingate Anaerobic Test (WAnT) became one of the most convenient tests used to evaluate anaerobic capacity and the effectiveness of anaerobic training programs for a variety of power sports. However, its use and interpretation as an evaluative measurement are limited because there are few published reference values derived from large numbers of subjects in nonathletic populations. We present reference values for the WAnT in Colombian healthy adults (aged 20-80 years old). The sample comprised 1,873 subjects (64% men) from Cali, Colombia, who were recruited for the study between 2002 and 2012. The 30-second WAnT was performed on a Monark ergometer. The WAnT resistance was set at 0.075 kp · kg(-1) body mass (BM). The mean absolute peak power (PP), relative PP normalized to the BM, and the fatigue index (FI%) were calculated using the LMS method (L [curve Box-Cox], M [curve median], and S [curve coefficient of variation]) and expressed as tabulated percentiles from 3 to 97 and as smoothed centile curves (P3, P10, P25, P50, P75, P90, P97). Mean ± SD values for the patients' anthropometric data were 38.1 ± 11.7 years of age, 72.7 ± 14.2 kg weight, 1.68 ± 0.09 m height, and 25.6 ± 4.2 body mass index. Our results show that mean absolute PP value, relative PP relative values normalized to BM, and FI were 527.4 ± 131.7 W, 7.6 ± 2.3 W · kg(-1), and 29.0 ± 15.7%, respectively. Men performed better than women in terms of PP and FI values. Nevertheless, the mean PP decreased with age and sex. Age-specific PP and FI normative values among healthy Colombian adults are defined. A more specific set of reference values is useful for clinicians and researchers studying anaerobic capacity in healthy adults.


Real-time tracking of bacterial membrane vesicles reveals enhanced membrane traffic upon antibiotic exposure.
Membrane vesicles are ubiquitous carriers of molecular information. A broad understanding of the biological functions of membrane vesicles in bacteria remains elusive because of the imaging challenges during real-time in vivo experiments. Here, we provide a quantitative analysis of the motion of individual vesicles in living microbes using fluorescence microscopy, and we show that while vesicle free diffusion in the intercellular space is rare, vesicles mostly disperse along the bacterial surfaces. Most remarkably, when bacteria are challenged with low doses of antibiotics, vesicle production and traffic, quantified by instantaneous vesicle speeds and total traveled distance per unit time, are significantly enhanced. Furthermore, the enhanced vesicle movement is independent of cell clustering properties but rather is associated with a reduction of the density of surface appendages in response to antibiotics. Together, our results provide insights into the emerging field of spatial organization and dynamics of membrane vesicles in microcolonies.


Two-dimensional gel analysis of the polypeptides precipitated by a polymorphic HLA-DR1,2,w6 monoclonal antibody: evidence for a third locus.
The SDR1 monoclonal antibody reacts only with cells which express the HLA-DR1, 2,w6 or w8 allogeneic specificities. Two-dimensional nonequilibrium pH gradient/sodium dodecyl sulfate polyacrylamide gel electrophoretic analyses of SDR1 immunoprecipitates from [35S]methionine biosynthetically labeled cells revealed the typical pattern of Ia antigens, namely two polypeptides of about 34kDa and 29kDa (designated epsilon and beta-3) as well as the "basic invariant spot" of about 31 kDa. The epsilon and beta-3 polypeptides were only weakly represented in similar analyses of immunoprecipitates performed using a monomorphic HLA-DR monoclonal antibody, TDR31.1. The epsilon and beta-3 polypeptides of B lymphoblastoid cell lines homozygous for HLA-DR2 and w6 were structurally polymorphic as judged by two-dimensional gel analyses. This polymorphism was independent of the HLA-DR specificity. It is concluded that the SDR1 antibody recognizes a polymorphic set of Ia antigens that are coded by a locus other than HLA-DR. These antigens probably also express the MT1 (DC1, LB12) alloantigenic specificity and are most likely the human equivalent of the murine I-A subregion antigens.


Sparse representation of brain aging: extracting covariance patterns from structural MRI.
An enhanced understanding of how normal aging alters brain structure is urgently needed for the early diagnosis and treatment of age-related mental diseases. Structural magnetic resonance imaging (MRI) is a reliable technique used to detect age-related changes in the human brain. Currently, multivariate pattern analysis (MVPA) enables the exploration of subtle and distributed changes of data obtained from structural MRI images. In this study, a new MVPA approach based on sparse representation has been employed to investigate the anatomical covariance patterns of normal aging. Two groups of participants (group 1:290 participants; group 2:56 participants) were evaluated in this study. These two groups were scanned with two 1.5 T MRI machines. In the first group, we obtained the discriminative patterns using a t-test filter and sparse representation step. We were able to distinguish the young from old cohort with a very high accuracy using only a few voxels of the discriminative patterns (group 1:98.4%; group 2:96.4%). The experimental results showed that the selected voxels may be categorized into two components according to the two steps in the proposed method. The first component focuses on the precentral and postcentral gyri, and the caudate nucleus, which play an important role in sensorimotor tasks. The strongest volume reduction with age was observed in these clusters. The second component is mainly distributed over the cerebellum, thalamus, and right inferior frontal gyrus. These regions are not only critical nodes of the sensorimotor circuitry but also the cognitive circuitry although their volume shows a relative resilience against aging. Considering the voxels selection procedure, we suggest that the aging of the sensorimotor and cognitive brain regions identified in this study has a covarying relationship with each other.


Inhibition of DNA polymerase alpha from leukemic and normal human cells by partially thiolated human deoxyribonucleic acids.
In continuing search for exploitable biochemical differences between cancer and normal cells at the level of DNA replication, leukemic and "normal" hematopoietic cells from four different, established human cell lines were grown in culture flasks, and both the DNA and the DNA polymerase alpha were isolated in each case from the harvested (5-10 g wet weight) cell pellets. The four selected cell lines included a "normal" lymphoblastoid B-cell line (RPMI-1788), a pre-B cell (NALM-6) and a T-cell (MOLT-4) acute lymphoblastic leukemias, and a promyelocytic leukemia (HL-60). The DNA polymerase alpha enzyme of the two B-cell lines (both the leukemic and the "normal") showed the usual sensitivity toward inhibition by aphidicolin, while those from the two other leukemic cell lines were remarkably resistant to the antibiotic. Partially thiolated polycytidylic acid (MPC) strongly inhibited only the DNA polymerase alpha of the "normal" cell line, whereas the corresponding enzymes of all three leukemic cell lines were relatively insensitive to MPC. In contrast, the partially thiolated DNAs derived from the leukemic cell lines more strongly inhibited the DNA polymerase alphas of the leukemic cell lines than that of the "normal" cell line. These results indicate the existence of some structural differences between the DNA polymerase alpha enzymes (as well as between the DNAs) of human cells of different lineage and, particularly, of leukemic vs. "normal" character; such differences could be exploited in the design of selective antitemplates for chemotherapy.


Oncological and functional outcomes of intersphincteric resection for low rectal cancer.
The intersphincteric resection technique has been used to extend the opportunity for sphincter preservation in patients with very low rectal cancer. The aim of this study is to assess the long-term oncological and functional outcomes of intersphincteric resection. Patients with extraperitoneal rectal cancer were treated and retrospectively chart reviewed. The oncological and functional outcomes were evaluated. Comparisons of the overall disease-free survival and recurrence were analyzed for the different surgical procedures. From July 2002 to August 2009, 162 patients with extraperitoneal rectal cancer were retrospectively chart reviewed. One-hundred one patients (62.3%) underwent low anterior resection, 26 patients (16%) received radical proctectomy and intersphincteric resection with coloanal anastomosis, and 23 (14.2%) had abdominoperineal resection. The sphincter preservation rate was 80%. In the intersphincteric resection group, overall survival rates at 3 and 5 y were 83% and 83%, and disease-free survival at 3 and 5 y were 82% and 76%, respectively. The mean stool frequency was 4.7 per 24 h. There were 38.1% of patients suffering from stool fragmentation, and 23.8% had nocturnal defecation. About one-third of the patients required antidiarrheal medications. Overall, 90.8% of patients were satisfied with the functional results of surgery. Our data show intersphincteric resection for low rectal cancer is feasible and safe. Preoperative radiotherapy may negatively affect symptom-specific quality of life.


Cerebrospinal Fluid Levels of sAPPα and sAPPβ in Lewy Body and Alzheimer's Disease: Clinical and Neurochemical Correlates.
We measured cerebrospinal fluid (CSF) levels of the soluble isoforms of amyloid precursor protein (APP; sAPPα sAPPβ) and other CSF biomarkers in 107 patients with Alzheimer's disease (AD), dementia with Lewy body dementia (DLB), Parkinson's disease dementia (PDD), and normal controls (NC) using commercial kits. DLB and PDD were combined in a Lewy body dementia group (LBD). No differences were observed in sAPPα and sAPPβ levels between the groups. Significant correlations were observed between sAPPα and sAPPβ and between sAPPβ and Mini-Mental State Examination scores in the total group analysis as well as when LBD and AD groups were analyzed separately. sAPPα and sAPPβ levels correlated with Aβ38, Aβ40, Aβ42, and Tau in the LBD group. In AD, sAPPα correlated with p-Tau and sAPPβ with Aβ40. The differential association between sAPPα and sAPPβ with Aβ and Tau species between LBD and AD groups suggests a possible relationship with the underlying pathologies in LBD and AD.


Elevated serum levels of pantropic p53 proteins in chromium workers.
This study investigated the possibility of applying serum pantropic p53 proteins in molecular epidemiologic studies, as a biomarker of environmental carcinogenesis. The serum levels of pantropic p53 proteins were determined in workers with past exposure to hexavalent chromium compounds. Thirty-one male workers occupationally exposed to hexavalent chromium compounds in the production of chromium compounds for 0 to 23 years served as the exposed group. The referents were 10 volunteers without work-related exposure to chemicals. In the determination of pantropic p53 proteins, commercially available kits for enzyme-linked immunosorbent assay were used which quantitatively detected both mutant and wild-type human p53 proteins. The serum level of pantropic p53 proteins was in the range of 116.4 to 1122.6 pg/ml for the exposed workers and of 117.4 to 305.8 pg/ml for the referents. Nineteen percent of the exposed workers had a high p53 protein level (6 out of 31) when compared with the referents. All but 1 of the 6 workers had been occupationally exposed to chromium compounds for more than 11 years. Two of the 3 workers with a past history of lung cancer also showed high levels. Our findings confirm that the application of p53 proteins as a biomarker of environmental carcinogenesis merits further exploration.


The functional significance of brain metallothioneins.
Metallothioneins (MTs) are ubiquitous low molecular weight proteins characterized by their abundant content of cysteines. Two MT isoforms, MT-I and MT-II, are expressed coordinately in all mammalian tissues. In the CNS, MT-I and MT-II are conspicuously absent from neuronal populations, yet abundant in fibrous and protoplasmic astrocytes. A newly identified brain-specific MT gene, MT-III, is predominantly expressed in zinc-containing neurons of the hippocampus and absent from glial elements. MTs have been implicated as regulator molecules in gene expression, homeostatic control of cellular metabolism of metals, and cellular adaptation to stress. MTs store and release essential metals, such as zinc and copper, maintaining the low intracellular concentration of free essential metals. Thus, MTs fulfill a regulatory capacity and influence transcription, replication, protein synthesis, metabolism, as well as other zinc-dependent biological processes. Because MT-III is particularly abundant in zinc-containing neurons of the hippocampus, it is likely to play an important role in neuromodulation by zinc-containing neurons and to act as a sink for free zinc. It may also play an etiologic role in various pathophysiological conditions associated with increased extracellular zinc. Studies demonstrating that MT-III prevents neuronal sprouting in vitro, appears to be down-regulated in Alzheimer's disease, and that MT-III "knockout" mice appear highly sensitive to kainateinduced seizures have focused growing attention on the etiologic role of MT-III in neurodegeneration.-Aschner, M. The functional significance of brain metallothioneins.


Could the Olfactory System Be a Target for Homeopathic Remedies as Nanomedicines?
Homeopathic remedies (HRs) contain odorant molecules such as flavonoids or terpenes and can lose their efficiency in presence of some competitive odors. Such similarities, along with extreme sensitivity of the olfactory system, widespread presence of olfactory receptors over all organic tissues (where they have metabolic roles besides perception of odors), and potential direct access to the brain through olfactory nerves (ONs) and trigeminal nerves, may suggest the olfactory system as target for HRs. Recent works highlighted that HRs exist in a dual form, that is, a still molecular form at low dilution and a nanoparticulate form at high dilution, and that remnants of source remedy persist in extremely high dilutions. From the literature, both odorants and nanoparticles (NPs) can enter the body through inhalation, digestive absorption, or through the skin, especially, NPs or viruses can directly reach the brain through axons of nerves. Assuming that HRs are recognized by olfactory receptors, their information could be transmitted to numerous tissues through receptor-ligand interaction, or to the brain by either activating the axon potential of ONs and trigeminal nerves or, in their nanoparticulate form, by translocating through axons of these nerves. Moreover, the nanoparticulate form may activate the immune system at multiple levels, induce systemic various biological responses through the pituitary axis and inflammation factors, or modulate gene expression at the cellular level. As immunity, inflammation, pituitary axis, and olfactory system are closely linked together, their permanent interaction triggered by olfactory receptors may thus ensure homeostasis.


A play-based intervention for children with ADHD: a pilot study.
Many children with attention deficit hyperactivity disorder (ADHD) have serious social and peer difficulties that can lead to adverse outcomes in adolescence and adulthood. To date, psychosocial treatments have produced poor outcomes in reducing social impairments commonly associated with ADHD. This study aimed to examine the efficacy of a new intervention designed to improve the play and social skills of children with ADHD and their playmates within the natural context of play. Participants included children (aged 5-11 years) diagnosed with ADHD, age-matched typically developing playmates (n=14/group) and parents of children with ADHD. The intervention involved seven weekly video-recorded free-play sessions; video feed-forward/feedback and therapist- and peer-modelling were used to promote social play. The Test of Playfulness was used as a pre-/post-test measure. Data were subjected to Rasch analysis to calculate measure scores on interval level; dependant sample t-test and Cohen-d calculations were used to measure effect. A dependant samples t-test revealed that both children with ADHD (t=8.1; d.f.=13; P<0.01) and their playmates (t=6.9; d.f.=13; P<0.01) improved in their social play. Results demonstrated a large effect in improving the social play of children with ADHD (d=1.5) and their playmates (d=1.3). Results support the use of play, video feed-forward/feedback techniques, therapist- and peer-modelling and parent involvement as an effective means to develop the social play skills of children with ADHD. Further larger-scale research is required.


Lattice dynamics and superconductivity in cerium at high pressure.
We have measured phonon dispersion relations of the high-pressure phase cerium-oC4 (α' phase with the α-uranium crystal structure) at 6.5 GPa by using inelastic x-ray scattering. Pronounced phonon anomalies are observed, which are remarkably similar to those of α-U. First-principles electronic structure calculations reproduce the anomalies and allow us to identify strong electron-phonon coupling as their origin. At the low-pressure end of its stability range, Ce-oC4 is on the verge of a lattice-dynamical instability and possibly a charge density wave. The superconducting transition temperatures of the fcc, oC4, and mC4 phases of Ce have been calculated, and the superconductivity observed experimentally by Wittig and Probst is attributed to the oC4 phase.


The olive constituent oleuropein exhibits anti-ischemic, antioxidative, and hypolipidemic effects in anesthetized rabbits.
Thgoal of this study was to evaluate the efficacy of the antioxidant olive constituent, oleuropein, on infarct size, oxidative damage, and the metabolic profile in rabbits subjected to ischemia. Oleuropein, 10 or 20 mg/(kg x d), was administered to 8 groups that consumed a normal or hypercholesterolemic diet for 6 wk or only the higher dose for 3 wk. Circulating levels of malondialdehyde, protein carbonyl, nitrite+nitrate, cholesterol, triglycerides, SOD activity, and the metabolic profile were measured using 1H NMR spectra. In rabbits that consumed the normal diet, the infarct size (percentage of infarct to risk areas) was reduced by the administration of 10 mg oleuropein/(kg x d) (16.1 +/- 2.9%) or 20 mg oleuropein/(kg x d) for 3 wk (21.7 +/- 2.2%) or for 6 wk (24.3 +/- 1.3%) compared with the control group (48.05 +/- 2.0%, P < 0.05). Only the higher dose of 20 mg/(kg x d) reduced the infarct size in hypercholesterolemic rabbits (34.7 +/- 4.4% for 6 wk and 34.8 +/- 6.1% for 3 wk) compared with the cholesterol-fed control group (52.8 +/- 2.4%, P < 0.05). Oleuropein decreased the plasma lipid peroxidation product and protein carbonyl concentrations compared with the control groups, in which these factors increased relative to baseline due to ischemia and reperfusion. Furthermore, in rabbits administered oleuropein, RBC superoxide dismutase activity did not change during ischemia and reperfusion. This activity was significantly higher than in both control groups in which it was reduced by ischemia and reperfusion compared with baseline. Treatment for 6 wk with both doses of oleuropein reduced total cholesterol and triglyceride concentrations. 1H NMR spectra revealed a different profile of glycolysis metabolites in the oleuropein-treated groups compared with the controls. Oleuropein, for 3 or 6 wk, reduced the infarct size, conferred strong antioxidant protection and reduced the circulating lipids. This is the first experimental study in vivo that suggests the possibility of using an olive constituent in the treatment of ischemia.


Chromatic induction in space and time.
The color appearance of a light depends on variation in the complete visual field over both space and time. In the spatial domain, a chromatic stimulus within a patterned chromatic surround can appear a different hue than the same stimulus within a uniform surround. In the temporal domain, a stimulus presented as an element of a continuously changing chromaticity can appear a different color compared to the identical stimulus, presented simultaneously but viewed alone. This is the flash-lag effect for color, which has an analog in the domain of motion: a pulsed object seen alone can appear to lag behind an identical pulsed object that is an element of a motion sequence. Studies of the flash-lag effect for motion have considered whether it is mediated by a neural representation for the moving physical stimulus or, alternatively, for the perceived motion. The current study addresses this question for the flash-lag effect for color by testing whether the color flash lag depends on a representation of only the changing chromatic stimulus or, alternatively, its color percept, which can be altered by chromatic induction. baseline measurements for spatial chromatic induction determined the chromaticity of a flashed ring within a uniform surround that matched a flashed ring within a patterned surround. Baseline measurements for the color flash-lag effect determined the chromaticity of a pulsed ring presented alone (within a uniform surround) that matched a pulsed ring presented in a sequence of changing chromaticity over time (also within a uniform surround). Finally, the main experiments combined chromatic induction from a patterned surround and the flash-lag effect, in three conditions: (1) both the changing and pulsed rings were within a patterned chromatic surround; (2) the changing ring was within a patterned surround and the pulsed ring within a uniform surround; and (3) the changing ring was within a uniform surround and the pulsed ring within a patterned surround. the flash-lag measurements for a changing chromaticity were affected by perceptual changes induced by the surrounding chromatic pattern. Thus, the color shifts induced by a chromatic surround are incorporated in the neural representation mediating the flash-lag effect for color.


Testing an ecophysiological mechanism of morphological plasticity in pupfish and its relevance to conservation efforts for endangered Devils Hole pupfish.
Imperiled species that have been translocated or established in captivity can show rapid alterations in morphology and behavior, but the proximate mechanisms of such phenotypic changes are rarely known. Devils Hole pupfish (Cyprinodon diabolis) are endemic to a single desert pool and are characterized by a small body, large head and eyes, and lack of pelvic fins. To lessen the risk of extinction, additional populations of C. diabolis were established in artificial refuges. Yet, pupfish in these refuges rapidly shifted to a larger body, smaller head and eyes, and greater body depth. Here we examined how food availability and temperature, which differ between these habitats, influence morphological development in closely related Amargosa River pupfish (Cyprinodon nevadensis amargosae). We were interested in knowing whether these environmental factors could developmentally shift Amargosa River pupfish toward the morphology typical of pupfish in Devil's Hole. By regulating food ration, we created groups of pupfish with low, medium and high growth rates. Pupfish with low growth showed proportionally larger head and eyes, smaller body depth, and reduction in pelvic fin development. Elevated temperature further inhibited pelvic fin development in all treatments. Pupfish in the low growth group also showed reduced levels of thyroid hormone, suggesting a possible physiological mechanism underlying these morphological changes. To test this mechanism further, pupfish were reared with goitrogens to pharmacologically inhibit endogenous thyroid hormone production. Pupfish given goitrogens developed larger heads and eyes, shallower bodies, and reduced pelvic fins. Taken together, our results suggest that changes in environmental factors affecting the growth and thyroid hormone status of juvenile pupfish may play a developmental role in generating the morphological differences between C. diabolis in Devil's Hole and the refuges. These findings illustrate the need to incorporate a mechanistic understanding of phenotypic plasticity into conservation strategies to preserve imperiled fishes.


Performance and reliability of the SYBR Green I based assay for the routine monitoring of susceptibility of Plasmodium falciparum clinical isolates.
The performance and the reliability of a SYBR Green I fluorescence-based assay to assess drug susceptibility in routine monitoring were evaluated in 138 Plasmodium falciparum clinical samples. Blood samples were studied for susceptibility to four antimalarial drugs by the SYBR Green I based assay, with the traditional [(3)H]-hypoxanthine isotopic assay as a reference. The two methods were observed to have similar geometric means of IC50s and IC90s, and high correlation (r=0.93 for IC50s and r=0.94 for IC90s) for the drugs tested. The strength of agreement estimated by using concordance coefficient correlation was from almost perfect to substantial for IC50s. Our data demonstrate (i) the reliability of a simple, rapid and easy to use fluorescence-based assay for the routine monitoring of susceptibility of P. falciparum clinical isolates, and (ii) the possible switch from the traditional in vitro drug sensitivity assay to the SYBR Green I method, because previous data acquired by the isotopic assay were comparable with those obtained by the SYBR Green I method. We conclude that this assay will provide an easier method for testing drug susceptibility of malaria parasites, especially in malaria-endemic countries, where there is massive implementation of new artemisinin-based combination therapies.


Anthropogenic chlorofluoromethanes in the greenland and norwegian seas.
The concentrations of two industrially produced chlorofluoromethanes, CCl(3)F(F-11) and CCl(2)F(2)(F-12), have been measured in the water column and in the marine atmosphere of the Greenland and Norwegian seas. Measurable concentrations of these two chlorofluoromethanes have penetrated to the deep basins of both of these regions, and the general characteristics of their vertical distributions are similar to those of the bomb-produced radioisotopes injected into the atmosphere on a similar time scale. The data have been fitted to a time-dependent box model based on deep convective mixing in the Greenland Sea and lateral exchange between the deep basins. The model calculations for the two chlorofluoromethanes in the Greenland Sea give similar results, with a time scale for deep convection of about 40 years. The time scale for lateral mixing between the deep Greenland Sea and the deep Norwegian Sea is estimated to be 20 to 30 years, although the agreement between the calculations for the two chlorofluoromethanes is limited by analytical uncertainties at the low concentrations found in the deep Norwegian Sea and by uncertainties in the model assumptions.


Atypical chromosome 22q11.2 deletions are complex rearrangements and have different mechanistic origins.
The majority (99%) of individuals with 22q11.2 deletion syndrome (22q11.2DS) have a deletion that is caused by non-allelic homologous recombination between two of four low copy repeat clusters on chromosome 22q11.2 (LCR22s). However, in a small subset of patients, atypical deletions are observed with at least one deletion breakpoint within unique sequence between the LCR22s. The position of the chromosome breakpoints and the mechanisms driving those atypical deletions remain poorly studied. Our large-scale, whole genome sequencing study of >1500 subjects with 22q11.2DS identified six unrelated individuals with atypical deletions of different types. Using a combination of whole genome sequencing data and fiber-fluorescence in situ hybridization, we mapped the rearranged alleles in these subjects. In four of them, the distal breakpoints mapped within one of the LCR22s and we found that the deletions likely occurred by replication-based mechanisms. Interestingly, in two of them, an inversion probably preceded inter-chromosomal 'allelic' homologous recombination between differently oriented LCR22-D alleles. Inversion associated allelic homologous recombination (AHR) may well be a common mechanism driving (atypical) deletions on 22q11.2.


Hippocampal size predicts rapid learning of a cognitive map in humans.
The idea that humans use flexible map-like representations of their environment to guide spatial navigation has a long and controversial history. One reason for this enduring controversy might be that individuals vary considerably in their ability to form and utilize cognitive maps. Here we investigate the behavioral and neuroanatomical signatures of these individual differences. Participants learned an unfamiliar campus environment over a period of three weeks. In their first visit, they learned the position of different buildings along two routes in separate areas of the campus. During the following weeks, they learned these routes for a second and third time, along with two paths that connected both areas of the campus. Behavioral assessments after each learning session indicated that subjects formed a coherent representation of the spatial structure of the entire campus after learning a single connecting path. Volumetric analyses of structural MRI data and voxel-based morphometry (VBM) indicated that the size of the right posterior hippocampus predicted the ability to use this spatial knowledge to make inferences about the relative positions of different buildings on the campus. An inverse relationship between gray matter volume and performance was observed in the caudate. These results suggest that (i) humans can rapidly acquire cognitive maps of large-scale environments and (ii) individual differences in hippocampal anatomy may provide the neuroanatomical substrate for individual differences in the ability to learn and flexibly use these cognitive maps. © 2013 Wiley Periodicals, Inc.


The influence of family history of diabetes on disease prevalence and associated metabolic risk factors among Sri Lankan adults.
To describe the influence of family history on diabetes prevalence and associated metabolic risk factors in a nationally representative sample from Sri Lanka. A cross sectional national survey was conducted among 5000 adults in Sri Lanka. Family history was evaluated at three levels: (1) parents, (2) grandparents (paternal and maternal) and (3) siblings. A binary-logistic regression analysis controlling for confounders (age, gender, BMI and physical activity) was performed in all patients with 'presence of diabetes' as the dichotomous dependent variable and using family history in father, mother, maternal grandmother/grandfather, paternal grandmother/grandfather, siblings and children as binary independent variables. The sample size was 4485, mean age was 46.1 ± 15.1 years and 39.5% were males. In all adults, the prevalence of diabetes was significantly higher in patients with a family history (23.0%) than those without (8.2%) (P < 0.001). When family history was present in both parents, the prevalence of diabetes was 32.9%. Presence of a family history significantly increased the risk of diabetes [odds ratio (OR): 3.35, 95% confidence interval (CI): 2.78-4.03], obesity (OR: 2.45, 95% CI: 1.99-2.99), hypertension (OR: 1.25, 95% CI: 1.08-1.45) and metabolic syndrome (OR: 2.28, 95% CI: 1.97-2.63). In all adults, the presence of a family history of diabetes in a father (OR: 1.29, 95% CI: 1.02-1.63), mother (OR: 1.23, 95% CI: 1.11-1.36), paternal grandfather (OR: 1.27, 95% CI: 1.14-1.41), siblings (OR: 4.18, 95% CI: 3.34-5.22) and children (OR: 5.47, 95% CI: 2.93-10.19) was associated with a significantly increased risk of developing diabetes. Family history and diabetes had a graded association in the Sri Lankan population, because the prevalence increased with the increasing number of generations affected. Family history of diabetes was also associated with the prevalence of obesity, metabolic syndrome and hypertension. Individuals with a family history of diabetes form an easily identifiable group who may benefit from targeted interventions.


The association between medication use and gait in adults with intellectual disabilities.
Adults with intellectual disabilities (ID) often have polypharmacy and often use antipsychotics. Both polypharmacy and antipsychotics have a negative effect on gait in the general population, but this has not been studied in adults with ID. These negative effects may add to pre-existing gait disturbances in adults with ID and increase the risk for adverse health outcomes in this population. Therefore, the aim of this study is to investigate the difference in gait parameters between adults with ID with and without polypharmacy and between adults with ID using and not using antipsychotics. The gait parameters of 31 participants were collected with the GAITRite walkway, a pressure sensitive walkway measuring spatial and temporal gait parameters, in addition to information about personal characteristics, prescribed medication and presence of polypharmacy. After adjustment for sex and body mass index, participants with polypharmacy had a significantly shorter step length [polypharmacy B (SE) = -0.079 (0.034), P = 0.03], shorter stride length [polypharmacy B (SE) = -0.157 (0.069), P = 0.03] and longer double support time [polypharmacy B (SE) = 0.0004 (0.0001), P = 0.047]. Participants using antipsychotics had a significantly longer double support time [antipsychotic use B (SE) = 0.0003 (0.0002), P = 0.019]. This study showed for the first time that both polypharmacy and using antipsychotics are associated with gait in adults with ID. The differences seem to resemble a more cautious gait. Further investigation with larger study samples, additional medication types and dosages are needed to acquire more insight in this important topic.


Food availability limits avian reproduction in the city: An experimental study on great tits Parus major.
The altered ecological and environmental conditions in towns and cities strongly affect demographic traits of urban animal populations, for example avian reproductive success is often reduced. Previous work suggests that this is partly driven by low insect availability during the breeding season, but robust experimental evidence that supports this food limitation hypothesis is not yet available. We tested core predictions of the food limitation hypothesis using a controlled experiment that provided supplementary insect food (nutritionally enhanced mealworms supplied daily to meet 40%-50% of each supplemented brood's food requirements) to great tit nestlings in urban and forest habitats. We measured parental provisioning rates and estimated the amount of supplementary food consumed by control and experimental nestlings, and assessed their body size and survival rates. Provisioning rates were similar across habitats and control and supplemented broods, but supplemented (and not control) broods consumed large quantities of supplementary food. As predicted by the food limitation hypothesis we found that nestlings in (a) urban control broods had smaller body size and nestling survival rates than those in forest control broods; (b) forest supplemented and control broods had similar body size and survival rates; (c) urban supplemented nestlings had larger body size and survival rates than those in urban control broods; and crucially (d) urban supplemented broods had similar body size and survival rates to nestlings in forest control broods. Our results provide rare experimental support for the strong negative effects of food limitation during the nestling rearing period on urban birds' breeding success. Furthermore, the fact that supplementary food almost completely eliminated habitat differences in survival rate and nestling body size suggest that urban stressors other than food shortage contributed relatively little to the reduced avian breeding success. Finally, given the impacts of the amount of supplementary food that we provided and taking clutch size differences into account, our results suggest that urban insect populations in our study system would need to be increased by a factor of at least 2.5 for urban and forest great tits to have similar reproductive success.


Two closely related endocytic proteins that share a common OCRL-binding motif with APPL1.
Mutations of the inositol 5' phosphatase oculocerebrorenal syndrome of Lowe (OCRL) give rise to the congenital X-linked disorders oculocerebrorenal syndrome of Lowe and Dent disease, two conditions giving rise to abnormal kidney proximal tubule reabsorption, and additional nervous system and ocular defects in the case of Lowe syndrome. Here, we identify two closely related endocytic proteins, Ses1 and Ses2, which interact with the ASH-RhoGAP-like (ASPM-SPD-2-Hydin homology and Rho-GTPase Activating Domain-like) domain of OCRL. The interaction is mediated by a short amino acid motif similar to that used by the rab-5 effector APPL1 (Adaptor Protein containing pleckstrin homology [PH] domain, PTB domain and Leucine zipper motif 1) APPL1 for OCRL binding. Ses binding is mutually exclusive with APPL1 binding, and is disrupted by the same missense mutations in the ASH-RhoGAP-like domain that also disrupt APPL1 binding. Like APPL1, Ses1 and -2 are localized on endosomes but reside on different endosomal subpopulations. These findings define a consensus motif (which we have called a phenylalanine and histidine [F&H] motif) for OCRL binding and are consistent with a scenario in which Lowe syndrome and Dent disease result from perturbations at multiple sites within the endocytic pathway.


Vertical Displacement in Unilateral Extension Base Flexible Removable Dentures.
The need for flexible thermoplastic denture base materials has increased due to patient demand for better esthetic outcomes. Designs aimed at improving esthetic outcomes can cause difficulties for prosthodontists, however, from the viewpoint of function and maintenance. Therefore, the purpose of this study was to investigate vertical displacement in unilateral extension base denture models, comparing that obtained by flexible removable dentures with that by conventional metal clasp dentures. Models of unilateral extension base flexible removable dentures for mandibular defects were prepared. Periodontal ligament and jaw mucosa were simulated using a silicone impression material. Four types of flexible removable denture, with or without a metal rest, and two metal clasp dentures made of acrylic resin as a conventional design were used as dental prostheses. The amount of vertical displacement in the defect areas was measured under a load of 50 N at the first and second molars. Among the 6 types of dentures investigated, the amount of vertical displacement was greater with flexible removable dentures than with metal clasp dentures. This vertical displacement tended to decrease significantly, however, with the use of a metal rest with the flexible removable dentures. Esteshot with a metal rest, in particular, showed the smallest amount of displacement in the flexible removable dentures (first molar, 0.265±0.007 mm; second molar, 0.423±0.008 mm). These results indicate the importance of the application of rests in unilateral extension base flexible removable dentures. It may be useful to employ a metal rest in conjunction with a flexible removable denture to reduce load on the underlying mucosa, as is done with conventional partial dentures.


Reduced Expression of Membrane Complement Regulatory Protein CD59 on Leukocytes following Lung Transplantation.
Cellular protection against undesired effects of complement activation is provided by expression of membrane-bound complement regulatory proteins including CD59. This protein prevents membrane attack complex formation and is considered to be involved in graft accommodation. Also, CD59 downregulates CD4+ and CD8+ T-cell activation and proliferation. It is unknown whether CD59 expression is affected by transplantation. The aim of this study was to evaluate the quantitative CD59 antigen expression on distinct leukocyte subsets following lung transplantation (n = 26) and to investigate whether this differs from pretransplantation (n = 9). The results show that CD59 expression on leukocytes is significantly lower posttransplantation compared with healthy controls (p = 0.002) and pretransplantation (p < 0.0001). Moreover, the CD59 expression diminishes posttransplantation on all distinct lymphocyte subsets (p < 0.02). This effect appeared to be specific for CD59 since the expression of other surface markers remained stable or inclined following transplantation. The highest antigen expression posttransplantation was observed on CD4+ T cells and monocytes (p ≤ 0.002). These findings show that CD59 expression on leukocytes diminishes posttransplantation, which could result in decreased resistance against complement and enhanced T-cell activation. If such reduction in CD59 expression also occurs on endothelial cells from the transplanted organ, this could lead to a change into a prothrombotic and proinflammatory phenotype.


Smoking prevalence in 2010: why the healthy people goal is unattainable.
This study examined the changes in smoking initiation and cessation needed to realize the Healthy People 2010 national adult smoking prevalence objective (13%). Using data from the National Health Interview Surveys, we calculated smoking prevalence over time with a dynamic population demographics model, examining the effects of changes in smoking initiation and cessation. The draft objective is unattainable solely through decreases in smoking initiation. It could be achieved through smoking cessation alone only if cessation rates immediately increased by a factor of more than 3.5. Assuming plausible decreases in initiation and increases in cessation, the draft objective is virtually unattainable. The health objectives should challenge the status quo but be achievable. Formal analysis often can assist in establishing reasonable objectives.


Presenting features and molecular genetics of primary hyperparathyroidism in the paediatric population.
To describe the presenting features and molecular genetics of primary hyperparathyroidism (PHPT) in the paediatric population. Retrospective study of 63 children diagnosed with primary PHPT from 1998 to 2018. Compared to older children, infants were often asymptomatic (54% vs 15%, P = 0.002) with a milder form of PHPT. When symptomatic, children and adolescents mostly presented with non-specific complaints such as asthenia, depression, weight loss, vomiting or abdominal pain. A genetic cause of PHPT was identified in about half of this cohort (52%). The infancy period was almost exclusively associated with mutation in genes involved in the calcium-sensing receptor (CaSR) signalling pathway (i.e. CaSR and AP2S1 genes, 'CaSR group'; 94% of infants with mutations) whereas childhood and adolescence were associated with mutation in genes involved in parathyroid cell proliferation (i.e. MEN1, CDC73, CDKN1B and RET genes, 'cell proliferation group'; 69% of children and adolescents with mutations). Although serum calcium levels did not differ between the two groups (P = 0.785), serum PTH levels and the urinary calcium/creatinine ratio were significantly higher in 'cell proliferation group' patients compared to those in the 'CaSR group' (P = 0.001 and 0.028, respectively). Although far less common than in adults, PHPT can develop in children and is associated with significant morbidity. Consequently, this diagnosis should be considered in children with non-specific complaints and lead to monitoring of mineral homeostasis parameters. A genetic cause of PHPT can be identified in about half of these patients.


Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis.
Whole exome sequencing has become a pivotal methodology for rapid and cost-effective detection of pathogenic variations in Mendelian disorders. A major challenge of this approach is determining the causative mutation from a substantial number of bystander variations that do not play any role in the disease etiology. Current strategies to analyze variations have mainly relied on genetic and functional arguments such as mode of inheritance, conservation, and loss of function prediction. Here, we demonstrate that disease-network analysis provides an additional layer of information to stratify variations even in the presence of incomplete sequencing coverage, a known limitation of exome sequencing. We studied a case of Hereditary Spastic Paraparesis (HSP) in a single inbred Palestinian family. HSP is a group of neuropathological disorders that are characterized by abnormal gait and spasticity of the lower limbs. Forty-five loci have been associated with HSP and lesions in 20 genes have been documented to induce the disorder. We used whole exome sequencing and homozygosity mapping to create a list of possible candidates. After exhausting the genetic and functional arguments, we stratified the remaining candidates according to their similarity to the previously known disease genes. Our analysis implicated the causative mutation in the motor domain of KIF1A, a gene that has not yet associated with HSP, which functions in anterograde axonal transportation. Our strategy can be useful for a large class of disorders that are characterized by locus heterogeneity, particularly when studying disorders in single families.


Prospective study of preoperative factors predicting intraoperative difficulty during laparoscopic transperitoneal simple nephrectomy.
To prospectively study and identify, the preoperative factors which predict intraoperative difficulty in laparoscopic transperitoneal simple nephrectomy. Seventy seven patients (41 males and 36 females) with mean age of 43 ± 17 years, undergoing transperitoneal laparoscopic simple nephrectomy at our institute between February 2012 to May 2013 were included in this study. Preoperative patients' characteristics recorded were: Gender of patients, history of intervention, palpable lump, BMI, urine culture, side, size of kidney, fixity of kidney on USG, perinephric fat stranding on preoperative CT scan, periureteral fat stranding, perinephric collection, enlarged hilar lymph nodes, renal vascular anomalies, differential renal function on renogram. Preoperative factors of these patients were noted and intraoperative difficulty in the surgery was scored between 1 (easiest) to 10 (most difficult or open conversion) by a single surgeon (who was a part of all studies either as operating surgeon or assistant). Using SPSS 15.0 software, multivariate and univariate analysis was done. In multivariate analysis presence of pyonephrosis on preoperative evaluation and BMI < 25kg/m(2) were found to be statistically significant factors predicting intraoperative difficulty during laparoscopic simple nephrectomy. On univariate analysis following factors were associated with increased surgeon's score: Lower BMI, palpable kidney, pyonephrosis, history of renal intervention, perinephric fat stranding, right side, fixity of kidney on USG with surrounding structures. Our findings suggest that presence of pyonephrosis as identified on preoperative imaging and a BMI of less than 25 Kg/m(2) are the most significant factors predicting intraoperative difficulty during laparoscopic simple nephrectomy.


Inhaled corticosteroids for cystic fibrosis.
Reduction of lung inflammation is one of the goals of cystic fibrosis (CF) therapy. Inhaled corticosteroids (ICS) are often used to treat children and adults with CF. The rationale for this is their potential to reduce lung damage arising from inflammation, as well as their effect on symptomatic wheezing. It is important to establish the current level of evidence for the risks and benefits of ICS, especially in the light of their known adverse effects on growth. To assess the effectiveness of taking regular ICS, compared to not taking them, in children and adults with CF. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We requested information from pharmaceutical companies manufacturing inhaled corticosteroids and authors of identified trials.Date of most recent search of the Group's Trials Register: June 2008. Randomised or quasi-randomised trials, published and unpublished, comparing ICS to placebo or standard treatment in individuals with CF. Two independent authors assessed methodological quality of trials using established criteria and extracted data using standard pro formas. Thirty citations were identified by the searches, of which 25, representing 13 trials were eligible for inclusion. These 13 trials reported the use of ICS in 506 people with CF aged between 6 and 55 years. One trial was a withdrawal study in individuals who were already taking ICS. Methodological quality was difficult to assess from published information. Inclusion criteria varied between trials, as did type and duration of treatment and timing of outcome assessments. Objective measures of airway function were reported in most trials but were often incomplete. Significant benefit has not been conclusively demonstrated. Four trials systematically documented adverse effects and growth was significantly affected in one study using high doses. Evidence from these trials is insufficient to establish whether ICS are beneficial in CF, but withdrawal in those already taking them has been shown to be safe. There is some evidence they may cause harm in terms of growth. It has not been established whether long-term use is beneficial in reducing lung inflammation, which should improve survival, but it is unlikely this will be proven conclusively in a randomised controlled trial.


Identification of multiple proteins expressed in murine embryos as binding partners for the WW domains of the ubiquitin-protein ligase Nedd4.
Nedd4 is a member of a growing family of ubiquitin-protein ligases which consist of a lipid-binding domain, two to four WW domains and a C-terminal ubiquitin-protein ligase domain. The Nedd4 mRNA levels are developmentally regulated and Nedd4 protein is highly expressed in many mouse embryonic tissues. In this study we have used a far-Western screen to identify embryonic proteins that interact with the WW domains in mouse Nedd4. We report here identification of eight Nedd4 WW-domain-interacting proteins from mouse embryonic cDNA expression libraries. Two of the proteins are novel, while two have been identified previously as ligands for a WW domain. All of these proteins contain one or more PY motifs. In seven of the eight proteins, these PY motifs are necessary for their interaction with the WW domains of Nedd4. Using site-directed mutagenesis, and by using individual WW domains of Nedd4 as probes for far-Western analysis, we show that the three WW domains in Nedd4 interact with varying affinities with the PY motifs present in various Nedd4-binding proteins. These results provide evidence that Nedd4 can potentially interact with multiple proteins, possibly simultaneously, through its WW domains.


Adipose extracellular matrix remodelling in obesity and insulin resistance.
The extracellular matrix (ECM) of adipose tissues undergoes constant remodelling to allow adipocytes and their precursor cells to change cell shape and function in adaptation to nutritional cues. Abnormal accumulation of ECM components and their modifiers in adipose tissues has been recently demonstrated to cause obesity-associated insulin resistance, a hallmark of type 2 diabetes. Integrins and other ECM receptors (e.g. CD44) that are expressed in adipose tissues have been shown to regulate insulin sensitivity. It is well understood that a hypoxic response is observed in adipose tissue expansion during obesity progression and that hypoxic response accelerates fibrosis and inflammation in white adipose tissues. The expansion of adipose tissues should require angiogenesis; however, the excess deposition of ECM limits the angiogenic response of white adipose tissues in obesity. While recent studies have focused on the metabolic consequences and the mechanisms of adipose tissue expansion and remodelling, little attention has been paid to the role played by the interaction between peri-adipocyte ECM and their cognate cell surface receptors. This review will address what is currently known about the roles played by adipose ECM, their modifiers, and ECM receptors in obesity and insulin resistance. Understanding how excess ECM deposition in the adipose tissue deteriorates insulin sensitivity would provide us hints to develop a new therapeutic strategy for the treatment of insulin resistance and type 2 diabetes.